Brain Tumours and Cancer Stem Cells Flashcards Preview

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Flashcards in Brain Tumours and Cancer Stem Cells Deck (35)
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1
Q

Are all brain tumours malignant?

A

No, but they are likely to be life threatening due to they location.

2
Q

Are brain tumours more common in children or adults?

A

Children

3
Q

What are the cells of the central nervous system?

A

Glial cells and Neuronal cells

4
Q

What are Gliomas?

A

Gliomas are tumours that originate from the glial cells of the brain. Astrocytomas and Oligodendrocytomas.

5
Q

Why do adults not usually develop neuronal tumours?

A

By adulthood most of the neurons with the brain are developed, there is no longer a pool of dividing progenitor required for tumour formation. Tumours come for proliferating tissues.

6
Q

In adults what cells are the primary source for brain tumours?

A

Glial cells. These are still dividing. Astrocystomas come from astrocytes, oligodendrocytomas come from oligodendrocytes.

7
Q

How are neuronal tumours named?

A

Some by morphology but others from the location in which they are found.

8
Q

Where is the most common site for neuronal tumours?

A

In the cerebellum at the back of the brain.

9
Q

Why is radiotherapy more damaging for children than adults?

A

Radiotherapy destroys all the dividing cells, adults have fewer neuronal cells and thus damage is reduced. Growth in children is stunted from the point of treatment.

10
Q

Why is chemotherapy ineffective for the treatment of brain tumours?

A

The blood-brain barrier is a difficult obstacle to overcome.

11
Q

What is the most common brain tumour of children?

A

Medulloblastoma

12
Q

What classes of tumour are there?

A

Classical Tumour (big nuclei, not much cytoplasm)

Nodular Tumour Desmoplastic

Large cell version

13
Q

What is Turcot’s syndrome?

A

Turcot syndrome is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It predisposes individuals to colon cancer and certain brain tumours.

14
Q

What is Gorlin’s syndrome?

A

Gorlin’s syndrome predisposes individuals to develop non-melanoma skin cancer (BCC, basal cell carcinoma) and brain tumours.

15
Q

What two syndromes, with different genetic pathways can lead to similar brain tumours?

A

Turcot and Gorlin’s syndrome.

16
Q

How does Turcot syndrome affect the colon?

A

In the colon FAP (familial adenomatous polyposis) occurs.

17
Q

What method of inheritance does Turcot syndrome show?

A

Autosomal Dominant

18
Q

Why can Turcot syndrome be thought of as two syndromes?

A

APC (Adenomatous polyposis coli), in the Wnt pathway, mutations results in predisposition to colon cancer and medulloblastoma.

MMR (Mismatch repair) mutations results in predisposition to colon cancer and glioblastoma.

19
Q

If β-catenin and TCF are activated what occurs?

A

They drive the expression of genes that promote cell proliferation.

20
Q

Without a signal how does β-catenin function within the cell?

A

β-catenin is involved in a destruction complex. β-catenin is phosphorylated and degraded, it doesn’t go to the nucleus and is not involved in proliferation.

21
Q

If a wnt signal activates β-catenin what occurs?

A

β-catenin builds up and activates genes and proliferation.

22
Q

What does a mutation in APC result in?

A

Mutations in APC prevent the degradation of β-catenin. Even in the absence of the signal, the β-catenin is not degraded, it goes to the nucleus and drives cell proliferation.

23
Q

How do mutations in the wnt pathway lead to cancer?

A

β-catenin is stabilised/activated, this associates with Tcf/Lef and activates gene expression including c-Myc.

This leads to irregular proliferation and cell control within the brain and the colon.

24
Q

What inheritance pattern does Gorlin’s syndrome exhibit?

A

Autosomal Dominant

25
Q

What is the receptor for Shh?

A

Shh (Sonic hedgehog) binds to its receptor Ptch

26
Q

What happens to the Wnt/β-catenin pathway in the absence of wnt and β-catenin?

A

When wnt is absent, β-catenin is bound by a ‘destruction complex’ which induces protein kinases CK1γ and GSK-3β.

The protein kinases phosphorylate β-catenin, targeting it for ubiquitination and degradation in the proteasome.

When β-catenin is absent, transcriptional co-receptors bind to TCF transription factors which prevents the expression of certain genes.

27
Q

What happens to the Wnt/β-catenin pathway in the presence of wnt and β-catenin?

A

The wnt protein binds to the transmembrane receptor Frizzled. This causes a signal to be transmitted across the membrane by Frizzled and LRP, activating them.

Activation of Frizzled and LRP causes protein kinases CK1γ and GSK-3β to associate with the membrane. The protein kinases then phosphorylate the tail of the activated LRP.

Next, the intracellular signalling protein Dishevelledand the proteinAxin are recruited to the cytoplasmic tails of LRP and Frizzled.

This prevents the formation of the destruction complex, meaning β-catenin accumulates in the cytoplasm.

β-catenin the moves into the nucleus. β-catenin binds to TCF, displacing the co-receptors. This enables the target genes to be expressed

28
Q

What is the role of shh?

A

Shh (Sonic hedgehog) is a key factor needed for the proliferation of granule neuron precursors of the cerebellum during normal development.

Shh binds to PTCH, derepressing Smo. Smo releases Gli to the nucleus to act as a transcriptional activator.

29
Q

What are the effects of a mutation in the PTCH receptor?

A

Mutations in PTCH stop the receptor inhibiting Smo. Therefore Shh is no longer needed to bind to PTCH.

Smo is de-repressed and stimulates growth (normally Shh stops PTCH from inhibiting Smo).

Smo can signal regardless of PTCH as it is no longer repressed by it. The mutation has stopped PTCH from inhibiting Smo.

The growth pathway is activated, granules form (root of proliferative disease). Gli TF levels increase within the nucleus.

30
Q

What does SUFU do?

A

SUFU takes the key receptor, GLI out of the pathway, switching proliferation off.

This SUFU mutation is found in 12% of patients.

31
Q

What did experiments on PTCH1+/1 heterozygote mice show?

A

3-7% of the PTCH1+/- heterozygote mice developed tumours.

32
Q

What did experiments on PTCH1+/1 heterozygote mice crossed with p53-/- show?

A

All PTCH1+/1 p53-/- spontaneously develop tumours. This shows that simply disrupting the Shh pathway is SUFFICIENT to predispose these animals to develop the granule brain tumour of the cerebellum: MB.

33
Q

How do wnt and shh tumours differ anatomically?

A

Shh tumours tend to be away from the brain stem.

Wnt tumours tend to be right up against the brain stem.

34
Q

Why are wnt tumours not cerebellum tumours?

A

They are brainstem tumours that push their way into the cerebellum.

Experiment:

Target mutated B-catenin to cerebellum = No tumours

Target mutated B-catenin to the brainstem = Disrupted migration, proliferation in dorsal brain tumours. When p53 is knocked out 15% of mice developed classic medulloblastoma after 290 days.

35
Q
A